Mechanism of Disease

TTR Formation

Transthyretin (TTR) is mostly produced by the liver and circulates in the blood. In people with ATTR-CM, tetrameric TTR dissociates into folded monomers which is the rate-limiting step of amyloid fibril formation.

Amyloid Fibril Formation

Monomers acquire a partially misfolded conformation, and self-assemble into soluble oligomeric aggregates, leading ultimately to the formation of insoluble amyloid fibrils.

Development of Hypertrophic Cardiomyopathy

Ventricular infiltration of these amyloid fibrils leads to chambers’ progressive thickening and the progressive development of hypertrophic cardiomyopathy.

Therapeutic strategy to stabilise tetrameric TTR

A therapeutic strategy for ATTR-CM involves enhancing the kinetic stability of tetrameric TTR by molecules able to bind the T4 pocket, such as acoramidis, thus preventing the early stage of TTR dissociation.